Structure-function characterization of the transition zone in the intervertebral disc.

Understanding the structure-function relationship in the intervertebral disk (IVD) is crucial for the development of novel tissue engineering strategies to regenerate IVD and the establishment of accurate computational models for low back pain research. A large number of studies have improved our knowledge of the mechanical and structural properties of the nucleus pulposus (NP) and annulus fibrosus (AF), two of the main regions in the IVD. However, few studies have focused on the AF-NP interface (transition zone; TZ). Therefore, the current study aims to, for the first time, characterize the cyclic and failure mechanical properties of the TZ region under physiological loading (1, 3, and 5%s-1 strain rates) and investigate the structural integration mechanisms between the NP, TZ, and AF regions. The results of the current study reveal significant effects of region (NP, TZ, and AF) and strain rates (1, 3, and 5%s-1) on stiffness (p < 0.001). In addition, energy absorption is significantly higher for the AF compared to the TZ and NP (p <0.001) as well as between the TZ and NP (p <0.001). The current research finds adaptation, direct penetration, and entanglement between TZ and AF fibers as three common mechanisms for structural integration between the TZ and AF regions. STATEMENT OF SIGNIFICANCE: Despite a large number of studies that have mechanically, structurally, and biologically characterized the nucleus pulposus (NP) and annulus fibrosus (AF) regions, few studies have focused on the NP-AF interface region (known as Transition Zone; TZ) in the IVD; hence, our understanding of the TZ structure-function relationship is still incomplete. Of particular importance, the cyclic mechanical properties of the TZ, compared to the adjacent regions (NP and AF), are yet to be explored and the precise nature of the structural integration between the NP and AF via the TZ region is not yet known. The current study explores both the mechanical and structural properties of the TZ region to ultimately identify the mechanism of integration between the NP and AF.

Toward a mechanically biocompatible intervertebral disc: Engineering of combined biomimetic annulus fibrosus and nucleus pulposus analogs.

Intervertebral disc (IVD) degeneration and accompanying lower back pain impose global medical and societal challenges, affecting over 600 million people worldwide. The IVD complex fibrocartilaginous structure is responsible for the spine biomechanical function. The nucleus pulposus (NP), composed of swellable glycosaminoglycan (GAG), transfers compressive loads to the surrounding fiber-reinforced annulus fibrosus (AF) lamellae, which stretches under tension. Together, these substructures allow the IVD to withstand extremely high and complex loads. Key to mimic the complete disc must consider the properties of its substructures. This study presents three novel substructures-a biomimetic silk-reinforced composite lamella for the AF, a GAG analog for the NP, and a novel biomimetic combined AF-NP construct. The biomimetic AF demonstrates nonlinear, hyperelastic, and anisotropic behavior similar to the native human AF, while the NP analog demonstrates mechanical behavior similar to the human NP. The synergized biomimetic AF-NP demonstrates similar behavior to the unconfined NP, with significantly increased deformations indicating improved performance. Validation of the AF-NP construct mechanics using a finite element model yields results compatible with native human IVD under various physiological loadings. The ability of our AF-NP construct to mimic the native IVD offers a revolutionary concept for the potential development of a fully functional IVD.

The mechanical behavior of silk-fibroin reinforced alginate hydrogel biocomposites - Toward functional tissue biomimetics.

Soft tissues are constructed as fiber-reinforced composites consisting of structural mechanisms and unique mechanical behavior. Biomimetics of their mechanical behavior is currently a significant bioengineering challenge, emphasizing the need to replicate structural and mechanical mechanisms into novel biocomposite designs. Here we present a novel silk-based biocomposite laminate constructed from long natural silk and fibroin fibers embedded in an alginate hydrogel matrix. Controlling the mechanical features of these laminates were studied for different fiber volume fractions (VF) and orientations using unidirectional tensile tests. Three material systems were investigated having different fiber orientations: longitudinal (0°), transverse (90°), and cross-plied (0/90°). The general behavior of the biocomposite laminates was anisotropic hyperelastic with large deformations. Longitudinal fibroin laminates have shown a tensile modulus of 178.55 ± 14.46 MPa and tensile strength of 18.47 ± 2.01 MPa for 0.48 VF. With similar VF, cross-plied fibroin laminates demonstrated structural shielding ability, having a tensile modulus and tensile strength of 101.73 ± 8.04 MPa and 8.29 ± 1.63 MPa for only a third of the VF directed in the stretching direction. The stress-strain behavior was in a similar range to highly stiff native human soft tissues such as ligament and meniscus. These findings demonstrate the potential of the fibroin fiber-reinforced biocomposites to mimic the mechanics of tissues with a quantitatively controlled amount of fibers and designed spatial arrangement. This can lead to new solutions for the repair and replacement of damaged functional and highly stiff soft tissues.

Postoperative changes after surgical mesh hernia repair: a pitfall in interpretation of 18F-FDG PET-CT.

OBJECTIVE: A number of case reports have demonstrated FDG uptake around mesh prostheses after hernia repair surgery. This study characterizes FDG PET-CT findings after hernia repair with synthetic mesh in a series of cancer patients. MATERIALS AND METHODS: FDG PET-CT studies were reviewed for increased FDG uptake consistent with CT appearances of post-surgical hernia repair in cancer patients. The findings were correlated with clinical data and follow-up studies. RESULTS: 53 PET-CT studies in 22 patients (18 males, 31-79 years) were identified. Surgery for repair of inguinal (n = 14), ventral (n = 5) or umbilical (n = 3) hernia was performed, 4-204 months prior to PET-CT. FDG avidity was focal or linear in the region of the anterior abdominal or pelvic wall (mean SUV max 4.0 ± 2.3). Corresponding nonspecific CT findings included soft tissue thickening (n = 18), fat infiltration (n = 20) and fluid collection (n = 19) in the region of the omentum, adjacent to or in the inner abdominal or pelvic wall at the surgical site. Linear hyper-dense structures (n = 9) or metallic clips (n = 8) seen on CT suggested benign postoperative changes. In 10/12 (83.3%) patients with repeat PET-CT, FDG uptake remained unchanged, one showed more diffuse uptake and another showed reduced uptake on follow-up. There was neither significant change in CT appearance at the surgical site in these 12 patients, nor in 3 additional patients with only CT follow-up. Another 3 patients had previous CT demonstrating hernia at the same location. CONCLUSION: With increasing use of synthetic mesh, awareness of variations in FDG PET-CT appearance is important to avoid false interpretation in cancer patients.

Stair climbing test post-stroke: feasibility, convergent validity and metabolic, cardiac, and respiratory responses.

BACKGROUND: The 6-minute walk test (6MWT) and treadmill walk tests (TMW) are commonly used to assess post-stroke patients (PSP) aerobic capacity. However, these tests are not without their limitations (e.g. limited sensitivity to change and the use of external pacing). Therefore, there is a need for additional tools to assess PSP aerobic capacity. OBJECTIVE: To establish the feasibility, convergent validity, and metabolic, cardiac, and respiratory responses of a stair climbing test (SC), among chronic PSP. METHODS: Nineteen chronic PSP conducted SC, TMW, and 6 MWT. Metabolic (oxygen consumption - VO2), cardiac (heart rate), and respiratory (ventilation volume, breathing frequency, and tidal volume) measures were established. Adverse events were documented. Correlations established the convergent validity of the SC test. A repeated measures analysis of variance was performed to compare the participant's physiological responses at the end of the various tests. RESULTS: SC is feasible and safe, as all participants completed the test with no adverse events. The SC demonstrated convergent validity as numerous associations were found between SC and TMW, and 6 MWT. Metabolic, cardiac, and respiratory responses to the SC were significantly higher than these of the TMW and 6 MWT (e.g. VO2= 13.43 ± 2.19, 11.01 ± 2.0, and 11.26 ± 1.87 ml/kg/min, respectively) (P < 0.05). CONCLUSIONS: SC is a feasible and valid test within chronic PSP. SC is more metabolically demanding than TMW and 6 MW and therefore, may enable appropriate endurance capacity measurement, especially for high functioning PSP. Negotiating stairs is a common community ambulation requirement. Therefore, it is appropriate to incorporate SC test in PSP testing battery.

Model-based correction for scatter and tailing effects in simultaneous 99mTc and 123I imaging for a CdZnTe cardiac SPECT camera.

An advantage of semiconductor-based dedicated cardiac single photon emission computed tomography (SPECT) cameras when compared to conventional Anger cameras is superior energy resolution. This provides the potential for improved separation of the photopeaks in dual radionuclide imaging, such as combined use of (99m)Tc and (123)I . There is, however, the added complexity of tailing effects in the detectors that must be accounted for. In this paper we present a model-based correction algorithm which extracts the useful primary counts of (99m)Tc and (123)I from projection data. Equations describing the in-patient scatter and tailing effects in the detectors are iteratively solved for both radionuclides simultaneously using a maximum a posteriori probability algorithm with one-step-late evaluation. Energy window-dependent parameters for the equations describing in-patient scatter are estimated using Monte Carlo simulations. Parameters for the equations describing tailing effects are estimated using virtually scatter-free experimental measurements on a dedicated cardiac SPECT camera with CdZnTe-detectors. When applied to a phantom study with both (99m)Tc and (123)I, results show that the estimated spatial distribution of events from (99m)Tc in the (99m)Tc photopeak energy window is very similar to that measured in a single (99m)Tc phantom study. The extracted images of primary events display increased cold lesion contrasts for both (99m)Tc and (123)I.

Can upright myocardial perfusion imaging be used alone with a solid-state dedicated cardiac camera?

AIM: The novel solid state dedicated cardiac cameras provide fast high resolution cardiac imaging. The D-SPECT camera enables semi-reclining (upright) positioning, increasing comfort and potentially reducing movement during myocardial perfusion imaging. Physicians are generally familiar with supine imaging and the different positioning in upright imaging could potentially cause diagnostic challenges. The aim of this study was to compare the upright and supine imaging for diagnostic ability to assess Physician confidence and determine any artefacts in upright imaging. METHODS: Fifty-five patients underwent myocardial perfusion imaging on the D-SPECT camera in both upright and supine positions. Where both images showed the same defects the 2 techniques were regarded as equally diagnostic. Where only one set showed a defect this was regarded as artefact and was defined as non-diagnostic. The location and cause of the artefact was recorded. RESULTS: In 13 /55 patients either form of imaging was regarded as equally diagnostic. In 24/55 the supine images revealed artefact affecting interpretation. The reasons for this were most frequently large BMI, motion and gut uptake. In 18/55 upright images were considered non-diagnostic. In 16/18 this was due to an infero-apical defect seen in female patients (14/16) with raised BMI and/or large breasts. CONCLUSION: Upright myocardial perfusion imaging on D-SPECT shows a common artefact (in up to 1/3 of cases) in the infero-apical region mainly in overweight female patients. Getting acquainted with this artefact this may increase Physician confidence in reporting, similarly as to conventional supine imaging. Indeed, some of the artefacts seen on supine imaging appear less commonly with upright imaging. Thus, upright imaging can potentially be used alone for diagnosis with D-SPECT. Performance of both supine and upright imaging can be reserved for overweight patients thereby minimizing impact on scanning time and clinical throughput in busy departments.

Mechanical efficiency and balance in adolescents and young adults with cerebral palsy.

Mechanical efficiency (ME) during stair-climbing measures ambulation ability. This study investigated the relationship between ME and age, anthropometric, functional walking, and balance parameters in 52 adolescents with cerebral palsy (CP), age 13.5-23.3 yrs, who participated in an intervention study to improve walking. Measurements included ME, 6-min and 10-m walk tests and the Berg balance scale (BBS). Walk test measures correlated significantly with ME, as expected, as did BBS (r=0.68) and age (r=0.51). The multiple correlation coefficient with both age and BBS increased to 0.80. The measurements were divided into two groups of low (<40, n=19) and high (>40, n=33) BBS scores. Repeating regression analyses, demonstrated that in the low BBS group ME was significantly related to BBS, but not age, in contrast to opposite results in the high BBS group. Regressions were calculated for each of the 14 items of the BBS with ME. For the whole group, 12 items correlated significantly, but only three in the high BBS group (one leg standing, reach while standing and tandem standing). In the low BBS group 10 of the items correlated significantly, with the former three ranking near the top. Balance is an important component of ambulation in children with CP. Mobility in those scoring>40 is related to age, but in those more deficient in balance (<40) mobility is more closely associated with balance than age. Effective therapy to improve walking in younger children might incorporate more balance-focused exercises, similar to those related to BBS items strongly associated with ME.

Imaging of bone metastases in prostate cancer: an update.

Assessing bone metastases is often beyond the scope of plain - film radiography, and nuclear imaging in particular with bone scintigraphy has proved the mainstay for detection of bony disease for over 40 years. Bone scanning with 99mTechnetium - labeled diphosphonates relies on the detection of pathological osteoblastic response elicited from malignant cells. This technique offers the advantage of whole body examination, low cost, availability and high sensitivity. However, it suffers from relative low specificity. The addition of single-photon emission computed tomography (SPECT) to bone scintigraphy has markedly improved the diagnostic benefit. Although the accuracy of SPECT is significantly higher than that of planar scintigraphy, there is still room for improvement of anatomic localization and morphological characterization, a limitation that has currently been mainly overcome with the upcoming of combined SPECT-CT (computed tomography). Positron emission tomography (PET), a modality with higher spatial resolution than that of SPECT can be particularly helpful in detecting small lesions. Moreover, PET imaging using various specific radiotracers has the advantage of detecting malignant disease in both bone and soft tissues. It is highly sensitive mainly in detecting early bone marrow as well as for diagnosing lytic bony metastases and can be also reliably used to monitor therapy response. In this review, we present the current role of SPECT and PET in the imaging of skeletal metastases from prostate cancer.

G protein coupled receptors -in silico drug discovery and design.

In silico drug discovery is a complex process requiring flexibility and ingenuity in method selection and a careful validation of work protocols. GPCR in silico drug discovery poses additional challenges due to the paucity of crystallographic data. This paper starts by reviewing selected GPCR in silico screening programs reported in the literature, including both structure-based and ligand-based approaches. Particular emphasis is given to library design, binding mode selection, process validation and compound selection for biological testing. Following literature review, we provide insights into in silico methodologies and process workflows used at EPIX to drive over 20 highly successful screening and lead optimization programs performed since 2001. Applications of the various methodologies discussed are demonstrated by examples from recent programs that have not yet been published.

Random perturbation: a potential aid in treatment of children with cerebral palsy.

BACKGROUND AND PURPOSE: The motor behaviour of children with cerebral palsy (CP) can be viewed in terms of a stable mode with very little flexibility that prevents adaptation to tasks. We hypothesized that the use of random perturbations (RP) would weaken excessive stability, introduce flexibility and enhance the effects of physical treatment. The objective was to evaluate the contribution of RP to gross motor function and mechanical efficiency (MEg) during intensive physiotherapy in children with CP. METHODS: A convenience sample of 20 children with CP (mean age 8.2, range: 5.9-12.9 yrs) were matched by age and GMFCS level, and randomly assigned to structured intensive treatment (SIT) or to SIT + RP groups. Groups received one month of daily treatment. RP was applied by engine-induced random passive cycling for upper and lower limbs for up to 10 min in a 90-min treatment session. Gross Motor Function Measure (GMFM)-66 and gross mechanical efficiency (MEg) during stair climbing (MEg) were measured before and after treatment. RESULTS: GMFM-66 scores increased by about 1.0 in both groups. However, external work and MEg increased significantly more in SIT + RP than SIT. The increase in MEg in SIT + RP was independent of the level of motor function at baseline. CONCLUSION: The addition of RP in treatment of children with CP may have weakened previously established stereotypical motor patterns and introduced flexibility, thereby improving mechanical efficiency of a complex motor task. RP may enhance the effects of intensive treatment.

Method of analysing the performance of self-paced and engine induced cycling in children with cerebral palsy.

PURPOSE: To develop a method of quantifying the features of cycling in children with CP by comparing them to typically developed children, and to demonstrate the applications of this tool for evaluating treatment effects in children with CP. METHODS: Twenty-seven typically developed children and 51 with CP, classified by their gross motor function levels, were studied. Angular velocities were measured during self-paced active cycling and during passive cycling imposed by an electrically powered stationary cycle. Angular velocities were compared with the gross motor function levels, Modified Ashworth Scale and the Adductor Tone Rating. RESULTS: Significant differences between children with CP and those typically developed demonstrated in passive mode that the cycling task is sensitive to differences in resistance offered by the subjects. Active and passive cycling velocities differ significantly between groups classified by their functional levels (p < 0.01). Children with CP in the mild group showed no differences from typically developed children. The correlations between passive cycling and clinical tests were significant and higher at higher speeds (r = 0.62). Correlations with anthropometric measurements for the typically developed group associated the cycling task with growth and development, and for children with CP with motor control adjustments and impairments. CONCLUSIONS: Measuring of these two cycling modes could be applicable in assessing lower extremity function in children with CP and changes following interventions.

PET/CT for atherosclerotic plaque imaging.

Atherosclerosis is one of the leading causes of morbidity and mortality in the world. Rupture of atherosclerotic plaques and thrombi formation are the primary mechanisms of myocardial infarction or cerebrovascular accident. Angiography is considered to represent the gold standard technique for imaging of the arterial lumen. However, in recent years it has been realized that the primary determinant of the atherosclerotic plaque stability is the composition of the plaque and other imaging modalities have been suggested. The purpose of this review is to briefly summarize the knowledge accumulated to present date regarding the potential role of fluodeoxyglucose imaging in the assessment of atherosclerosis and to compare this modality to additional available imaging approaches for the detection of vulnerable plaques.

Do current treatment protocols adequately prevent airway remodeling in children with mild intermittent asthma?

BACKGROUND: Asthma treatment per Global Initiative for Asthma (GINA) guidelines targets airway remodeling and achievement of normal lung function. OBJECTIVE: To study inhaled steroid therapy on airway remodeling and achievement of normal lung function. SUBJECTS AND SET UP: Asthmatic patients were followed over 5 years . The children were divided into two groups. Group I (148 children-treated group) consisted of all the children using inhaled steroids on a regular basis and group II (50 children-untreated group) included patients with mild intermittent asthma who did not use inhaled steroids and were treated with bronchodilators as needed. Detailed medication and compliance history were recorded and the children underwent regular pre- and post-bronchodilator spirometry and physician examination. RESULTS: The incidence of airways remodeling as defined by the low FEV1/FVC post-bronchodilator was markedly increased over the 5-year period in the untreated group compared to the treated group. In the treated group the FEV1/FVC ratio post-bronchodilator decreased from 35% to 20.9% (P<0.009%) compared with the untreated group where the number of children with low FEV(1)/FVC post-bronchodilator increased from 10% to 28% by the end of the study period. CONCLUSION: Patients with mild asthma who do not receive regular inhaled steroids are at increased risk for airway remodeling. Therefore, we recommend that children with mild intermittent asthma undergo regular pulmonary function testing and that if any deterioration is detected in the FEV1/FVC ratio post-bronchodilators; preventative inhaled corticosteroid therapy be initiated.

The added value of spiral computed tomographic angiography after lung scintigraphy for the diagnosis of pulmonary embolism.

OBJECTIVES: The objectives of this study were to evaluate the added clinical value of spiral computed tomographic angiography (CTA) after ventilation-perfusion lung scintigraphy (V/Q) for the management of patients with suspected pulmonary embolism (PE). METHODS: Of 987 patients who had V/Q during 2001, 64 patients (6%) had CTA performed for further evaluation. V/Q and CTA findings were retrospectively analyzed by 2 clinicians who were blinded to the patients' outcome. Patient management was determined based on clinical and V/Q data and was reassessed after the addition of CTA data. RESULTS: CTA was performed in 2 patients with normal V/Q, 16 patients with low probability, 28 patients with intermediate, 4 patients with high probability, and 14 patients with nonconclusive V/Q. Three patients (19%) with low probability, 9 (32%) with intermediate probability, 4 (29%) with nonconclusive, and 4 (100%) with high probability V/Q had PE diagnosed by CTA. CTA findings changed the management in 2 patients (13%) with low probability, 15 (54%) with intermediate probability, and 4 (29%) with nonconclusive V/Q. CONCLUSION: In our institution, V/Q remains the main imaging modality for evaluation of patients with clinically suspected PE. CTA was performed after V/Q in 6% of patients. Patients with intermediate probability and those with nonconclusive V/Q, and to a much lesser extent, patients with low probability V/Q could benefit from the addition of CTA after V/Q. In patients with normal V/Q and those with high-probability V/Q, the addition of CTA does not seem to influence patient management.

Serum levels of sex hormones and corticosterone throughout 4- and 5-day estrous cycles in Fischer 344 rats and their simulation in ovariectomized females.

Among inbred strains of rats, the Fischer 344 (F344) is commonly used in immunological and behavioral studies. However, little is known about patterns of sex hormones and corticosterone (CORT) secretion throughout the estrous cycle in this strain, which is characterized by a marked CORT response to stress and variable length of cycles. In the current study, using radioimmunoassays, we assessed serum levels of progesterone, estradiol, LH, testosterone, prolactin and CORT, at 1-h intervals throughout the estrous cycle in F344 female rats with 4- and 5-day cycles, as well as in males. Vaginal smears were obtained from 268 females for 15 consecutive days to determine individual length of the estrous cycle and the exact estrous phase upon blood withdrawal, which was conducted once in each rat on the 12th day of smearing. The results indicated that both 4- and 5-day cyclers have two distinct and marked surges of progesterone, one on proestrus day and the other on diestrous-1 day. Testosterone levels in 5-day cyclers peaked on diestrus-3, one day earlier than in 4-day cyclers. Daily peak levels of CORT gradually increased from estrus day to proestrous day, whereas daily nadir levels of CORT remained unchanged. To simulate the natural kinetics of specific sex hormones in ovariectomized females, different doses of estradiol, progesterone, testosterone, prolactin or CORT were injected s.c. or i.p., or 90-day sustained release pellets containing different doses of estradiol or progesterone were implanted. The findings indicated dose- and time-dependent effects, suggesting regimens for modeling the estrous cycle or replacement therapy.

Ventricular mapping during atrial and ventricular pacing. Relationship of multipotential electrograms to ventricular tachycardia reentry circuits after myocardial infarction.

AIMS: Conduction through separated myocyte bundles causes multipotential electrograms and reentrant ventricular tachycardia. We hypothesized that without initiating tachycardia, the reentry region could be detected by analysing the change in multipotential electrograms during two different activation sequences. METHODS AND RESULTS: During catheter mapping and ablation in 16 patients with ventricular tachycardia late after infarction ventricular electrograms were recorded from 1072 sites during atrial and right ventricular paced ventricular activation. Multipotential electrograms were present during both activation sequences at 285 (27%) sites, during atrial pacing only at 159 (15%) sites and during right ventricular pacing only at 152 (14%) sites. Sites with multipotential electrograms during both activation sequences were more often related to a ventricular tachycardia circuit isthmus (43%) as compared to sites where such electrograms were present during one activation sequence (20%). Multipotential electrograms with >2 low amplitude deflections and a >100 ms difference in duration between the two activation sequences were infrequent but highly predictive of the reentry circuit. CONCLUSION: Regions with fixed multipotentials consistent with conduction block might be useful guides for ablation approaches that target large regions of the infarct, but are not sufficiently specific to be the sole guide for focal ablation approaches.